Solid peroral formulations known in the field of pharmaceuticals and foods include tablets, capsules, troches, chewable tablets, granules, and powders. However, not many formulations are designed for patient's ease in swallowing. There exists need for development of formulations which are easy to handle and easy to swallow for the aged, infants, and those having difficulty in swallowing. Tablets and capsules have drawbacks in that water is needed when they are taken. In addition, when the tablets are big or many tablets must be taken, patients have difficulty in swallowing or the tablets may become stuck within the pharynx or esophagus. These problems are very serious, especially to the aged, infants, and patients having difficulty in swallowing. Clogging of the throat sometimes suffocates such patients and medicines staying on the esophagus may cause inflammation. Troches are formulations which are gradually dissolved or disintegrated within the mouth for the application to the oral cavity or pharynx, and require no water. However, there is fear that they might stick within the pharynx or the esophagus when they are swallowed due to misuse. Chewable tablets need no water, being swallowed after chewing, but, they are not suitable for the aged or infants who have poor chewing force. Granules and powders require water for swallowing, and have drawbacks that they tend to stay in the oral cavity, choke the patient, and cause pain when they enter between false teeth.
In recent years, there is used a per tubam administration method in which medicines are given through a peroral or pernasal stomach tube catheter to a serious case having difficulty in swallowing. In practice, a prevailing method consists of injecting into the stomach tube catheter by use of a syringe a suspension prepared by adding crushed tablets or granules, or powdery medicines just as they are, to 20-30 ml of water. However, the procedures are complicated and the catheters are sometimes prone to clog since the inner diameter of the catheter is only 2-4 mm.
Against the foregoing background, there are known several formulations which are quickly disintegratable or soluble when put in the oral cavity or in water, and thus are suitable for the aged, infants, and those having difficulty in swallowing.
For example, Japanese Patent Publication (kokoku) No. 50445/1987 discloses a molded material having an open-matrix network structure obtained by filling molding pockets made of polyvinyl chloride sheet with an aqueous solution containing gelatin combined with a medicinal material, cooling and freezing the solution, and then freeze-drying the freezed solution. The publication describes that the open-matrix network structure has a density of 10-200 mg/ml, rapidly disintegrates within the oral cavity in 1-5 seconds, and is swallowed with sputum so as to prevent a patient who dislikes taking medicine from spitting it out.
In countries outside Japan, an intraoral soluble formulation known as Zydis (brand name) is commercialized by R. P. Scherer (England). The composition of the formulation is not known, but the formulation is manufactured by use of a freeze-drying process. The formulation manufactured by freeze-drying has the advantage of rapid disintegration, but it is fragile and brittle to such an extent that the hardness cannot be measured. Moreover, productivity of the formulation on an industrial scale is inferior because freeze-drying manufacturing equipment and long fabrication times are required.
International Patent Publication No. WO 93/12769 discloses an intraoral disintegratable formulation obtained by suspending a medicinal substance, lactose, and mannitol in an agar aqueous solution, solidifying the solution into a jelly state by charging the solution into molding pockets made of PTP (Press Through Package) sheet (made of polypropylene), drying the jelly under reduced pressure, and then sealing PTP-packaged products with aluminum foil. The obtained molded material has a density of 400-1000 mg/ml and is disintegrated in the oral cavity in 5-20 seconds. The publication describes that the molded material has a hardness of about 2 kg, and removal of the molded material from the PTP package does not result in cracking, crushing, or chipping. However, since the molded material has low strength as compared with conventional tablets, the material cannot be packaged in other than a PTP package, such as a bottle package. Also, productivity of the material on an industrial scale is inferior because of a long time needed for fabrication.
Several interoral disintegratable formulations which can be produced by a tableting method have been reported.
Japanese Patent Application Laid-Open (kokai) No. 271054/1993 discloses an intraoral disintegratable formulation which is obtained by tableting a mixture containing a pharmaceutically active ingredient, a carbohydrate, and a barely sufficient amount of water to moisten the surface of particles of the carbohydrate.
International Patent Publication No. WO 93/15724 discloses a rapid soluble tablet having two characteristics:
(1) the main component of the tablet is a medicinal additive having a high dissolution rate in water; and PA0 (2) during a process where tablets containing medicinal material are produced by use of a wet granulation method, a kneaded mixture of medicinal material and medicinal additives having a high dissolution rate in water is compression molded and then dried. PA0 (1) a molding method for producing tablets through a wet process, characterized by filling a mold with wet kneaded material and molding the material by use of compression molding; and PA0 (2) a molding method for producing tablets through a wet process, in which before wet tablets are compression-molded, powder is applied on the compressed surface or the compression-punched surface of wet tablets in order to prevent wet tablets from sticking when being compressed.
Japanese Patent Application Laid-Open (kokai) No. 218028/1994 discloses:
Japanese Patent Application Laid-Open (kokai) No. 19589/1996 discloses a method of manufacturing tablets by charging wet powder into holes for molding tablets, and forming the powder into the tablet shape by use of a mold for molding after application of a stick-prevention film on at least one surface of the above-mentioned wet powder within the hole.
Since these methods are wet tableting methods, they use a wetting agent during molding, and molding is performed under low pressure. Therefore, they provide porous tablets having proper voids after drying and which are soft and easily disintegrated.
However, because these methods involve charging and compressing wet powder having poor fluidity, they have the disadvantage that the amount of charged material varies and sticking often occurs. Moreover, they require special drying equipment for drying soft molded material while retaining shape, and productivity on an industrial scale is inferior.
To solve this problem, an interoral disintegratable formulation produced by a dry tableting method of superior productivity has been reported.
Japanese Patent Application Laid-Open (kokai) No. 310558/1993 discloses that a highly disintegratable solid formulation composition that enables reduction of the amount of other additives having high molding characteristics; for example, cellulose-based compounds, acrylic compounds, or gelatin and the like, is obtained by mixing mannitol or lactose, which has poor bonding and molding characteristics, and sorbitol powder or granule having a bulk density of 60 g/100 ml.
International Patent Publication No. WO 95/20380 discloses an intraoral disintegratable compression molded product having rapid disintegrability and solubility in the oral cavity which is obtained by incorporation of saccharides having low molding characteristics and saccharides having high molding characteristics. This publication discloses that the compression molded product has a hardness of 3-6 kg for a tablet of a diameter of 10 mm.phi. and a dissolution time of 15-25 seconds in the oral cavity. However, punching pressure is 50-400 kg/stroke (64-509 kg/cm.sup.2) and is rather low as compared with common punching pressure about 1000 kg/cm.sup.2. This suggests that the resultant molded product is brittle as compared with conventional tablets and has a very low falling impact strength.
A tablet obtained by molding under low punching pressure has a high disintegrability and dissolution rate but has a low hardness. A tablet obtained by molding under high punching pressure has a high hardness but has a low disintegrability and dissolution rate.
Conventional tablets have a high hardness that does not permit breakage during production and distribution; however, since they are designed to release the pharmaceutically active ingredient through disintegration and dissolution of the perorally administered tablets in the digestive tract, they are given no consideration of prompt disintegration and dissolution in the oral cavity. Consequently, the tablets exhibit insufficient disintegrability and solubility in the oral cavity. No known tablet exhibits rapid disintegration and dissolution in the oral cavity and, at the same time, high hardness.
Therefore, there remains need for tablets which exhibit rapid disintegration and dissolution when placed in the oral cavity or water and which do not collapse throughout the processes of manufacture and distribution.
An object of the present invention is to provide a quickly disintegratable compression-molded material which exhibits rapid disintegration and dissolution when placed in the oral cavity or water and which is endowed with high strength that does not permit collapse thereof throughout the processes of manufacture and distribution.
Another object of the present invention is to provide a method of excellent industrial productivity for the manufacture of a quickly disintegratable compression-molded material having excellent characteristics as described above, without need for intricate steps or complicated facilities, through use of a dry method which is employed in customary tableting methods.